Guidance on the identity, characterisation and conditions ... · Guidance on identity and characterisation of feed additives 3 EFSA Journal 20YY;volume(issue):NNNN 38 Table of contents

SCIENTIFIC OPINION

ADOPTED: DD MM YYYY PUBLISHED: dd mmmm yyyy AMENDED: dd mmmm yyyy

doi:10.2903/j.efsa.20YY.NNNN

www.efsa.europa.eu/efsajournal EFSA Journal 20YY;volume(issue):NNNN

Guidance on the identity, characterisation and 1

conditions of use of feed additives 2

EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP), Guido 3 Rychen, Gabriele Aquilina, Giovanna Azimonti, Vasileios Bampidis, Maria de Lourdes Bastos, 4

Georges Bories, Andrew Chesson, Pier Sandro Cocconcelli, Gerhard Flachowsky, Jürgen 5 Gropp, Boris Kolar, Maryline Kouba, Marta López Alonso, Secundino López Puente, Alberto 6 Mantovani, Baltasar Mayo, Fernando Ramos, Maria Saarela, Roberto Edoardo Villa, Robert 7

John Wallace, Pieter Wester, Montserrat Anguita, Jaume Galobart, Matteo Lorenzo Innocenti 8 and Paola Manini 9

Endorsed for public consultation on 16 May 2017 10

11

Abstract 12

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© European Food Safety Authority, 20YY 14

15

Keywords: identity, characterisation, feed additives 16

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Requestor: EFSA 18

Question number: EFSA-Q-2016-00823 19

Correspondence: [email protected] 20

21

22

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Guidance on identity and characterisation of feed additives

www.efsa.europa.eu/efsajournal 2 EFSA Journal 20YY;volume(issue):NNNN

Panel members: Gabriele Aquilina, Giovanna Azimonti, Vasileios Bampidis, Maria de Lourdes Bastos, 23 Georges Bories, Andrew Chesson, Pier Sandro Cocconcelli, Gerhard Flachowsky, Jürgen Gropp, Boris 24 Kolar, Maryline Kouba, Marta López Alonso, Secundino López Puente, Alberto Mantovani, Baltasar 25 Mayo, Fernando Ramos, Guido Rychen, Maria Saarela, Roberto Edoardo Villa, Robert John Wallace 26 and Pieter Wester. 27

Suggested citation: EFSA FEEDAP Panel (EFSA Panel on additives and products or substances used 28 in animal feed), 20YY. Guidance on the identity, characterisation and conditions of use of feed 29 additives. EFSA Journal 20YY;volume(issue):NNNN, 13 pp. doi:10.2903/j.efsa.20YY.NNNN 30

ISSN: 1831-4732 31

© 20YY European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on 32 behalf of European Food Safety Authority. 33

This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, 34 which permits use and distribution in any medium, provided the original work is properly cited and no 35 modifications or adaptations are made. 36

The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union.

37


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Table of contents 38

39 Endorsed for public consultation on 16 May 2017 ............................................................................. 1 40 Abstract ......................................................................................................................................... 1 41 Background and Terms of reference ................................................................................................ 4 42 Scope of the guidance .................................................................................................................... 4 43 1. Introduction ........................................................................................................................ 4 44 2. Section II: Identity, characterisation and conditions of use of the additive; methods of 45

analysis. ............................................................................................................................. 5 46 2.1. Identity of the additive ........................................................................................................ 5 47 2.1.1. Name of the additive ........................................................................................................... 5 48 2.1.2. Proposal for classification .................................................................................................... 5 49 2.1.3. Qualitative and quantitative composition (active substance/agent, other components, 50

impurities, batch to batch variation) ..................................................................................... 5 51 2.1.4. Impurities ........................................................................................................................... 6 52 2.1.5. Physical state of each form of the product ............................................................................ 7 53 2.2. Characterisation of the active substance(s)/agent(s) ............................................................. 7 54 2.2.1. Description ......................................................................................................................... 7 55 2.2.2. Relevant properties ............................................................................................................. 8 56 2.3. Manufacturing process, including any specific processing procedures ..................................... 9 57 2.3.1. Active substance(s)/agent(s) ............................................................................................... 9 58 2.3.2. Additive .............................................................................................................................. 9 59 2.4. Physical-chemical and technological properties of the additive ............................................... 9 60 2.4.1. Stability .............................................................................................................................. 9 61 2.4.2. Homogeneity .................................................................................................................... 10 62 2.4.3. Other characteristics ......................................................................................................... 10 63 2.4.4. Physico-chemical interactions in feed ................................................................................. 11 64 2.5. Conditions of use of the additive ........................................................................................ 11 65 2.5.1. Proposed mode of use in animal nutrition ........................................................................... 11 66 2.5.2. Information related to user safety ...................................................................................... 11 67 2.6. Methods of analysis and reference samples ........................................................................ 12 68 Glossary ...................................................................................................................................... 13 69 70

71




Background and Terms of reference 72

Regulation (EC) No 1831/2003 establishes the rules governing the Community authorisation of 73 additives for use in animal nutrition. Moreover, Regulation (EC) No 429/2008 provides detailed rules 74

for the implementation of Regulation (EC) No 1831/2003 as regards the preparation and the 75

presentation of applications and the assessment and the authorisation of feed additives. 76

The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP Panel) has adopted 77 a series of guidance documents which aim at complementing Regulation (EC) No 429/2008 to support 78

applicants in the preparation and submission of technical dossiers for the authorisation of additives for 79

use in animal nutrition according to Regulation (EC) No 1831/2003. 80

The European Food Safety Authority (EFSA) asked its FEEDAP Panel to: 81

1. identify from the current guidance documents, those that need to be updated, taking into 82 consideration the most recent scientific developments and the experience gained in the 83

assessment of feed additives; 84

2. update the guidance documents in need of revision accordingly; this activity can be conducted 85 in different rounds of activities on the basis of the priorities identified and on the feasibility of 86

the revision according the resources available; 87

3. taking into account the sensitivity and the relevance of some of the guidance documents 88 under revision and the entity of the revision itself (e.g. substantial or not), consider initiatives 89

like preparatory info-sessions or public consultations of the draft guidance documents. The 90

relevant comments received in either step will have to be considered and addressed if 91

appropriate in the final version of the guidance documents. 92

The first of the terms of reference was addressed by a statement of the FEEDAP Panel (EFSA FEEDAP 93 Panel, 2016), in which it was identified the need to update most of the guidance documents that it 94 produced and set priorities for this update. 95

This output addresses the second and third terms of reference with regards to the update of the 96 guidance documents dealing with the assessment of the identity and characterisation of feed 97 additives. 98

Scope of the guidance 99

This guidance document is intended to assist the applicant in the preparation and the presentation of 100 its application, as foreseen in Article 7.6 of Regulation (EC) No 1831/2003. This document does not 101 substitute for the obligation of an applicant to comply with the requirements of Regulation (EC) No 102 1831/2003 and its implementing rules. 103

In particular, this guidance document is intended to provide the information necessary to properly 104 identify and characterise a feed additive as required in Section 2 of Annex II and the relevant sections 105 of Annex III of Regulation (EC) No 429/2008. 106

1. Introduction 107

For the purpose of this guidance, the following definitions apply: 108

- Active substance: any substance or mixture of substances intended to be used as a feed 109 additive that provides the intended effect. 110

- Active agent: any microorganism intended to be used as a feed additive that provides the 111 intended effect. 112

- Preparations: A combination of the active substance with technological additives and other 113 substances or products which are incorporated to maintain the integrity of an active 114 substance but are not intended to perform a function in the feed in which the preparation is 115 to be incorporated. 116




- Feed additive: substances, microorganisms or preparations other than feed materials and 117 premixtures which are intentionally added to feed or water in order to perform one or more 118 functions mentioned in Article 5.3 of Regulation (EC) No 1831/2003. 119

The numbering in the sections below follows the same numbering as the Section 2 of Annex II of 120 Regulation (EC) No 429/2008. 121

Reasons should be given for the omission from the dossier of any data prescribed there. 122

2. Section II: Identity, characterisation and conditions of use of the 123

additive; methods of analysis. 124

2.1. Identity of the additive 125

The additive has to be fully identified and characterised. The studies described in this section must be 126 based on the final product(s) for which authorisation is sought. In-house identifiers should be avoided 127 unless embedded in third-party documents. In this case a statement is required to confirm that the 128 identifier(s) refers to the formulation(s) for which the claim is made. 129

2.1.1. Name of the additive 130

The name of the additive should be given. A proposal for a trade name may be made to be used 131 within the dossier to identify the additive. 132

2.1.2. Proposal for classification 133

The applicant should specify the intended effect which is expected following the use of the additive in 134 animal nutrition and make a proposal for the classification of the additive in one or more categories 135 and functional groups according to its main functions under Article 6 and Annex I of Regulation (EC) 136 No 1831/2003. 137

For ‘substances for reduction of the contamination of feed by mycotoxins’, the target mycotoxin(s) 138 should be specified. 139

Any data from other known uses of the identical active substances or agents (e.g. use in food, human 140 or veterinary medicine, agriculture and industry) must be provided. Any other authorisation as feed or 141 food additive, veterinary drugs or other kind of authorisations of the active substance(s)/agent(s) has 142 to be specified and properly referenced. 143

2.1.3. Qualitative and quantitative composition (active substance/agent, 144

other components, impurities, batch to batch variation) 145

The composition of the additive should be fully described, giving the proportion of the different 146 components by weight in the final product. In some cases, the active substance and the additive can 147 be considered as synonymous. 148

The applicant should propose a specification of the product as it relates to the concentration of the 149 active substance(s)/agent(s). Evidence should be provided by the analysis of at least five independent 150 production batches that this specification is satisfied in practice. If an application for an additive 151 covers different manufacturing methods or origins/sources, data from at least five batches should be 152 provided for each. 153

Data to establish the identity of the active substance(s)/agent(s) of the additive should be provided 154 using analytical methods with adequate characteristics of selectivity, sensitivity, accuracy and 155 precision. Where available, the methods used for the analytical determination of the active 156 substance(s)/agent(s) should be those with international recognition. Certificates of analysis indicating 157 the analytical values should be attached. Statements of compliance alone are not considered 158 sufficient. 159

- For microorganisms: number of viable cells expressed as colony forming units (CFU) per gram 160 should be determined. 161


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- For enzymes: each declared (main) activity should be described and the number of units of 162 each activity given. Other activities present should be also mentioned. The units of activity 163 should be defined preferably as µmoles of reaction product released per minute from the 164 substrate at a specified pH and temperature. 165

- For mineral substances: denomination and specification should follow internationally 166 recognised systems, where applicable. 167

- For ‘substances for reduction of the contamination of feed by mycotoxins’ which act by 168 binding, the mycotoxin binding capacity should be provided. 169

If the active component is a mixture of active substances or agents, each of which is clearly definable 170 (qualitatively and quantitatively), the active substance(s)/agent(s) must be described and the 171 proportions in the mixture given. 172

Other mixtures in which the constituents cannot be described by a single chemical formula and/or 173 where not all can be identified shall be characterised by the constituent(s) contributing to its activity. 174 Applicants should make reasonable efforts to fully describe the components of the mixture. 175

In case of the additives requested as consisting of preparations, quantitative data on the supporting 176 compound(s) should also be provided and the justification for inclusion given. 177

2.1.4. Impurities 178

The applicant should identify and quantify microbiological and chemical (including residual solvents) 179 impurities, substances with toxic or other undesirable properties that are not intentionally added and 180 do not contribute to the activity of the additive. The applicant should describe which impurities are 181 monitored on a routine basis, the frequency of testing and the action limits set for each monitored 182 impurity. Action limits for contaminants and impurities should respect existing legislation (e.g., 183 Directive 2002/32/EC, or specifications from European Union food additive authorisations) and 184 recommendations from internationally recognised sources when these are available (e.g., Joint 185 FAO/WHO Expert Committee on Food Additives (JECFA) specifications for enzymes; Commission 186 recommendation on the presence of deoxynivalenol, zearalenone, ochratoxin A, T-2 and HT-2 and 187 fumonisins in products intended for animal feeding, maximum levels for residual solvents used in 188 veterinary drugs (VICH guidance GL18)). 189

Analytical data on the impurities should be provided for at least three production batches. If an 190 application for an additive covers different manufacturing methods or origins/sources, data from at 191 least three batches should be provided for each. Certificates of analysis indicating the analytical values 192 should be provided; statements of compliance alone are not considered sufficient. The limits of 193 detection (LOD) and quantification (LOQ) of the analytical methods should be given. 194

Any substance produced via fermentation should be free of antimicrobial activities relevant to the use 195 of antibiotics in humans or animals. In addition the absence of production organisms in the additive 196 should be confirmed. For fermentation products in which the production strain has genes conferring 197 antibiotic resistance and for products produced with GMMs, the absence of the DNA from the 198 production strain in the final product should be demonstrated. For details on how to perform this 199 assessment, please refer to the Guidance on microbial characterisation. 200

As a guide the following should be considered as minimum requirements: 201

for microorganisms: microbiological contamination (at least Salmonella, enterobacteriaceae, 202 total yeasts and filamentous fungi, Bacillus cereus for bacilli) and, depending on the 203 fermentation media and excipients, mycotoxins,1 lead, mercury, cadmium and arsenic. 204

for fermentation products (not containing microorganisms as active agents): in addition to the 205 above, the extent to which spent growth medium is incorporated into the final product should 206 also be indicated. For products consisting of or produced by Gram negative bacteria, levels of 207 lipopolysaccharides (LPS) should be analysed in the final product. If the production strain is 208 known to be able to produce toxic compounds, the analysis should cover such compounds 209 (see Guidance on microbial characterisation). 210

1 The selection of mycotoxins for analysis should be made according to the different matrices, where appropriate.


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for plant derived substances: microbiological and botanical contamination, mycotoxins, dioxins 211 and the sum of dioxin and dioxin-like PCBs, pesticides,2 lead, mercury, cadmium and arsenic. 212

for animal derived substances: microbiological contamination, lead, mercury, cadmium and 213 arsenic. 214

for mineral substances, including compounds of trace elements: lead, mercury, cadmium , 215 arsenic and fluorine, dioxins and the sum of dioxin and dioxin-like PCBs. 216

for products produced by chemical synthesis and processes: all chemicals used in the 217 synthetic processes and any intermediate products remaining in the final product shall be 218 identified and their concentrations given. 219

2.1.5. Physical state of each form of the product 220

For liquid formulations, data on vapour pressure, specific weight and, where the additive is intended 221 to be used in water, (pH dependent) solubility or dispersability should be provided. 222

For solid formulations density, bulk density, dusting potential should be provided for at least three 223 batches of each formulation of the additive. For applications covering multiple sources of the additive, 224 these data should cover a representative range of the materials under application. 225

Dusting potential should be measured following recognised methods, e.g., rotating drum (Stauber-226 Heubach, DIN 55992, EN 15051) or continuous drop methods (EN 15051) and expressed in mg/m3 air. 227 When an occupational exposure limit is set or where there is a known or suspected toxicity after 228 inhalatory exposure, the concentration of the active substance in the dust and particle size of the 229 dust should be measured, preferably by laser diffraction, means or medians should be 230 expressed in relation to volume, to allow an exposure estimation to be made. 231

If the nature of the additive allows the possibility of the presence of nanoparticles initially a particle 232 size analysis of the additive by laser diffraction should be made. Should this indicate that more than 1 233 % of particles below 1 µm are present, this fraction should be further characterised by scanning 234 electronic microscopy (wet method). Results should be expressed as a proportion of total number of 235 particles. It should be clearly indicated if the product is a nanomaterial as defined by European 236 legislation.3 237

2.2. Characterisation of the active substance(s)/agent(s) 238

2.2.1. Description 239

A qualitative description of the active substance or agent should be given. This should include purity 240 and origin of the substance or agent, plus any other relevant characteristics. 241

Data to establish the identity of the active substance(s) should be provided using analytical methods 242 with adequate characteristics of selectivity, sensitivity, accuracy and precision. 243

An overview of the natural occurrence of the active substance(s) in materials used as feed/food 244 should be provided. 245

2.2.1.1. Chemical substances 246

Chemically defined substances should be described by generic name, chemical name according to 247 International Union of Pure and Applied Chemistry (IUPAC) nomenclature, other generic international 248 names and abbreviations and the Chemical Abstract Service (CAS) number and the European 249 INventory of Existing Commercial chemical Substances number (EINECS) and EC number, if 250

2 Residues specified under the undesirable substances directive (Directive 2002/32/EC) and any other pesticide residues of

potential concern to target animals and/or consumer safety. 3 Regulation (EU) No 1169/2011 of the European Parliament and of the Council of 25 October 2011 on the provision of food

information to consumers, amending Regulations (EC) No 1924/2006 and (EC) No 1925/2006 of the European Parliament and of the Council, and repealing Commission Directive 87/250/EEC, Council Directive 90/496/EEC, Commission Directive 1999/10/EC, Directive 2000/13/EC of the European Parliament and of the Council, Commission Directives 2002/67/EC and 2008/5/EC and Commission Regulation (EC) No 608/2004 OJ L 304, 22.11.2011, p. 18–63




available. The structural and molecular formula, the openSMILES notation and molecular weight must 251 be included. Where relevant, the isomeric forms should be given. Information on structurally related 252 substances should be included, when appropriate. 253

For chemically defined compounds used as flavourings, the FLAVIS number in connection with 254 relevant chemical group should be included. 255

For additives of plant origin the characterisation should include the scientific name of the plant of 256 origin and its botanical classification (family, genus, species, if appropriate subspecies). The parts of 257 the plant used to obtain the active substance(s) (e.g., leaves, flowers, seeds, fruits, tubers) should be 258 indicated. The identification criteria and other relevant aspects of the plants should be indicated. For 259 complex mixtures of many compounds obtained by an extraction process, it is recommended to follow 260 the relevant terminology such as essential oil, absolute, tincture, extract and related terms widely 261 used for botanically defined flavouring products to describe the extraction process. Reasonable efforts 262 should be made to identify and quantify all components of the mixture. A marker compound should be 263 selected which will allow the additive to be identified in the different studies. Information on the 264 variability in composition of comparable products should be provided. This could be done by reference 265 to published literature. 266

For natural products of non-plant origin, an equivalent approach to the above may be used. 267

Mixtures in which the constituents cannot be described by a single chemical formula and/or not all of 268 them can be identified shall be characterised by constituent(s) contributing to its activity. A marker 269 compound should be selected which will allow the additive to be identified in the different studies. 270

For clays data on elemental and mineralogical composition as well as information on the structure 271 should be provided by appropriate methods (e.g., atomic absorption spectrophotometry, X-Ray 272 diffraction, differential thermal analysis). 273

For enzyme and enzyme preparations, the number and systematic name proposed by the 274 International Union of Biochemistry (IUB) in the most recent edition of “Enzyme Nomenclature” shall 275 be given for each declared activity. For activities not yet included, a systematic name consistent with 276 the IUB rules of nomenclature shall be used. Trivial names are acceptable provided that they are 277 unambiguous and used consistently throughout the dossier, and they can be clearly related to the 278 systematic name and IUB number at their first mention. 279

When the active substance is supplied by a third party, the requirements/specifications (e.g. purity 280 and impurities) set by the applicant should be provided. 281

For chemical substances produced by fermentation, the microbial origin should also be described (see 282 2.2.1.2). 283

2.2.1.2. Microorganisms 284

The name and taxonomic classification of each microorganism should be provided (genus, species, 285 subspecies (if appropriate)), according to the latest published information in the International Codes 286 of Nomenclature (ICN). Microbial strains shall be deposited in an internationally recognised culture 287 collection having acquired the status of International Depositary Authority under the Budapest Treaty 288 (preferably in the European Union) and maintained by the culture collection for the authorised life of 289 the additive. A certificate of deposition from the collection, which shall specify the accession number 290 under which the strain is held, must be provided. 291

For all microorganisms, whether used as product or as production strain, the origin shall be provided 292 and any history of strain development should be indicated. It should be clearly stated whether the 293 microorganism is genetically modified or not within the meaning of the legislation (Directive 294 2001/18/EC). For GMMs, the genetic modification should be described. 295

For additives not consisting of and neither containing GMMs but for which GM microorganisms have 296 been used as a production strain, the applicant must provide a qualitative method of detection and 297 evidence demonstrating that there is no presence of recombinant DNA in the additive. 298

For details on how to address the above, refer to the Guidance on microbial characterisation. 299

2.2.2. Relevant properties 300


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Description of physical and chemical properties shall be given. Dissociation constant, pKa, melting 302 point, boiling point, density, vapour pressure, specific optical rotation, (pH dependent) solubility in 303 water and in organic solvents, Kow and Kd/Koc and any other relevant physical properties should be 304 provided, as appropriate. 305


Toxins and virulence factors 307

Toxins or virulence factors should be demonstrated to be absent or of no concern in microorganisms 308 used as additives or as production strain. 309

Antibiotic production and antibiotic resistance 310

Microorganisms used as additives or as a production strains, should be free of antibiotic activity or 311 should not be capable of producing antibiotic substances that are relevant as antibiotics in humans 312 and animals. 313

Microorganisms used as feed additives or as production strain should not add to the pool of 314 antimicrobial resistance genes already present in the gut bacterial population or otherwise increase 315 the risk of transfer of antimicrobial resistance. Consequently, all strains of bacteria should be tested 316 for susceptibility to antibiotics in use in human and veterinary medicine. 317

For details on how to address the above, refer to the Guidance on microbial characterisation. 318

2.3. Manufacturing process, including any specific processing 319

procedures 320

To define the critical points of the process that may have an influence on the purity and impurities of 321 the active substance/agent(s) or the additive, a detailed description of the manufacturing process 322 should be given. 323

2.3.1. Active substance(s)/agent(s) 324

A detailed description of the production process (e.g. chemical synthesis, fermentation, cultivation, 325 extraction from organic material or distillation and downstream purification steps) used in the 326 production of the active substance(s)/agent(s) of the additive should be submitted, if appropriate 327 supported by a flowchart. The use of any antimicrobial substances during the production process 328 should be declared. The composition of the fermentation/cultivation media shall be provided. 329

For GMMs used as source of additives and grown under contained conditions, Directive 2009/41/EC 330 applies. 331

2.3.2. Additive 332

A detailed description of the manufacturing process of the additive should be submitted. The key 333 stages in the preparation of the additive including the point(s) of introduction of the active 334 substance(s)/agent(s) and other components, and any subsequent process steps affecting the 335 additive should be provided, if appropriate supported by a flowchart. 336

2.4. Physical-chemical and technological properties of the additive 337

2.4.1. Stability 338

Stability is generally measured by the analytical follow-up of the active substance(s) (e.g., 339 mg/kg)/agent(s) (e.g., CFU/kg) or its activity (e.g., units of catalytic activity/kg) or effects (e.g., pellet 340 durability) during time. When the additive contains more than one active substance/agent, stability 341 should be assessed for each of the active substance(s)/agent(s). If specific effects are claimed for a 342 particular form of the additive (e.g., chelation) the stability of that specific form of the additive should 343


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be followed. For some chemical mixtures/extracts, stability may be assessed by monitoring the 344 concentration of one or more appropriate marker substances. Data should include at least one 345 observation at the beginning and one at the end of the storage period. 346

Stability studies are normally not required for mineral-based additives. 347

2.4.1.1. Shelf-life of the additive 348

Data should be produced which allows a realistic estimate of the shelf-life of each formulation of the 349 additive to be made. This should be based on studies performed under the recommended storage 350 conditions, which should be specified. Data should be provided from at least three batches of the 351 additive. 352

2.4.1.2. Stability of the additive used in premixtures and feedingstuffs 353

Stability studies in feedingstuffs are not required for silage additives and flavouring compounds. 354

The stability of the additive at the recommended inclusion level should normally be studied in 355 feedingstuffs manufactured and stored under practical conditions and, if relevant, in premixtures. The 356 quantitative and qualitative composition of the premixtures or the feedingstuffs used for the studies 357 should be given. When different formulations exist likely to impact on the stability of the additive, then 358 each formulation should be separately assessed. 359

For those additives intended to have an effect in feed, data provided should cover a representative 360 range of feedingstuffs (generally at least three) relevant to the use of the additive. The assessment of 361 stability in feed may be done by the maintenance of the effects. Duration of stability studies in 362 feedingstuffs should reflect the technological role of the additive. For those additives in which the 363 effect is dependent on a modification of the chemical structure of the active substance (e.g., 364 antioxidants) degradation products should also be identified and further assessed, if necessary. 365

For other additives, stability studies in feedingstuffs and premixtures should be of at least three and 366 six months’ duration, respectively. When the additive is intended to be incorporated via a premixture, 367 stability should be tested in one typical premixture containing trace elements. Stability studies in 368 feedingstuffs should reflect the diversity of rations for different animal species (generally at least 369 three). When relevant, stability in feedingstuffs should be determined in both mash and further 370 processed feed (e.g., pelleted or extruded) and should allow an assessment of the influence of the 371 processing. 372

2.4.1.3. Stability of the additive in water 373

The stability of the additive intended to be distributed via water for drinking should be studied at the 374 recommended inclusion level and under conditions simulating practical use (e.g., water temperature, 375 time) for a minimum duration of 48 h. These data should also take into consideration the presence of 376 excipients that could trigger growth of contaminating microorganisms. 377

For those silage additives intended for application through an aqueous suspension/solution, short term 378 stability (48 h) should be demonstrated. 379

2.4.2. Homogeneity 380

Homogeneity studies are not required for silage additives, flavouring compounds, colourings which 381 add or restore colour to feed or those that colour ornamental birds or fish and for those additives 382 intended to have an effect in feed for which efficacy has been demonstrated. 383

For the other additives, the capacity for homogeneous distribution of the feed additive in premixtures, 384 feedingstuffs or water should be demonstrated, as appropriate. As a guide, the content of the additive 385 should be analysed in a minimum of ten sub-samples from a single batch (of the premixture or 386 feedingstuff) and the coefficient of variation calculated. If homogeneity is demonstrated in the final 387 feedingstuff, there is no need to demonstrate homogeneity in premixtures. For those additives 388 intended to be distributed via the water for drinking, homogeneity studies are not required provided 389 that the additive is soluble/miscible at its proposed concentration of use. 390

2.4.3. Other characteristics 391




Any other relevant characteristics should be described. 392

2.4.4. Physico-chemical interactions in feed 393

Physico-chemical incompatibilities or interactions that could be expected in feed with feed materials, 394 carriers, other approved additives, or medicinal products must be documented. 395

For clays and other substances that act by binding and for all ‘substances for reduction of the 396 contamination of feed by mycotoxins’, evidence must be provided that the use of the additive under 397 the proposed conditions of use does not interfere with the analytical determination of mycotoxins in 398 feed. 399

The applicant should ensure that there is physico-chemical and biological compatibility between the 400 components of the preparation which is placed on the market and used as defined in Regulation (EU) 401 No 2015/327. 402

2.5. Conditions of use of the additive 403

2.5.1. Proposed mode of use in animal nutrition 404

The animal species or categories, age group or production stage of animals for which the additive is 405 intended to be used should be indicated. 406

The use and level of inclusion (as recommended, minimum or maximum concentration) in feed 407 materials, complete feedingstuffs (containing 12% moisture) or water for drinking should be defined, 408 as appropriate. If a particular use in complementary feedingstuffs or feed materials for some animal 409 species or categories is intended, the (daily) dose should be proposed and justified. For some 410 additives it may be more appropriate to propose a use level per head (or unit body weight) and day. 411 In such cases, the corresponding value expressed per kg complete feed should be estimated. 412

For additives intended to be used in water for drinking, the concentrations in water can be derived 413 from the proposed use level in feed, considering that for poultry, pigs and rabbits, the water intake 414 would be 2-3 times higher than feed intake (in dry matter). For ruminants and horses, the conversion 415 of feed concentration to water concentration should be done on the basis of the daily ration. 416 Concentrations of an additive cannot be consistently extrapolated from feed to water in ruminants 417 using a fixed ratio of feed to water intake. However, these concentrations can be converted to 418 amounts of a daily dose which can then be equally administered in a part of feed or water for 419 drinking. 420

The duration of administration and any withdrawal period should be indicated. 421

Possible contra-indications or restrictions in the handling or use of the additive should be mentioned. 422

2.5.2. Information related to user safety 423


A material safety data sheet formatted in accordance with the requirements of Regulation (EC) No 425 1907/20064 must be provided. If necessary, measures for the prevention of occupational risks and 426 means of protection during manufacture, handling, use and disposal should be proposed. All other 427 related provisions or assessments should be provided. 428


A classification according to Directive 2000/54/EC should be submitted. For microorganisms not 430 classified in group 1 in this Directive,5 information should be provided to customers to allow them to 431

4 Regulation (EC) No 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH),

establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. OJ L 396, 30.12.2006, p. 1.

5 In practice, in the absence of any entries under group 1, this information would be required for all microorganisms.




take the relevant protection measures for their workers, as defined in Article 3 (2) of the said 432 Directive. 433

2.5.2.3. Labelling requirements 434

Without prejudice to the labelling and packaging provisions laid down in Article 16 of Regulation (EC) 435 No 1831/2003, any specific labelling requirements and, where appropriate, specific conditions for use 436 and handling (including known incompatibilities and contraindications) and instructions for proper use 437 should be indicated. 438

2.6. Methods of analysis and reference samples 439

Methods of analysis to determine the active substance/agent in the additive itself and in premixtures 440 and feedingstuffs as appropriate should be submitted. These should be suitable for the official control 441 of the feed additive. If there are residues of concern, a method of analysis of the active substance 442 and/or its metabolites (including the marker residue) in the relevant tissues/products should be 443 provided. 444

These methods will be evaluated by the European Union Reference Laboratory (EURL). Details of the 445 requirements are specified in Regulation (EC) No 429/2008. Applicants should refer to the guidance 446 provided by the EURL. 447

Methods to determine the identity and the characteristics of the additive (composition of the additive, 448 impurities, physical and chemical properties) should be internationally recognised or otherwise fully 449 described. 450

451


https://ec.europa.eu/jrc/en/eurl/feed-additives/guidance-for-applicants

https://ec.europa.eu/jrc/en/eurl/feed-additives/guidance-for-applicants



References 452

EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP), 2016. Statement 453 on the establishment of guidelines for the assessment of additives from the functional group 454 ‘substances for reduction of the contamination of feed by mycotoxins’. EFSA 455 Journal 2010;8(7):1693. [8 pp.]. doi:10.2903/j.efsa.2010.1693 456

457

Glossary 458

Active agent: Any microorganism intended to be used as a feed additive that provides the 459

intended effect. 460

Active substance: Any substance or mixture of substances intended to be used as a feed additive 461

that provides the intended effect. 462

Feed additive: Substances, microorganisms or preparations other than feed materials and 463

premixtures which are intentionally added to feed or water in order to perform 464 one or more functions mentioned in Article 5.3 of Regulation (EC) No 465

1831/2003. 466

Formulation: The formulation is the final presentation of the feed additive intended to be 467

placed in the market. A formulation is the mixture of the active 468

substance(s)/agent(s) (or preparations) with other ingredients in order to 469

standardise the additive, improve its properties or modify its safety or efficacy. 470

Preparations: A combination of the active substance with technological additives and other 471

substances or products which are incorporated to maintain the integrity of an 472

active substance but are not intended to perform a function in the feed in which 473

the preparation is to be incorporated. 474

Specification: Set of requirements to be satisfied by all batches of a feed additive. This usually 475

includes a minimum content of the active substance(s)/agent(s). It could also 476 include maximum levels for certain impurities set on safety grounds. 477


http://dx.doi.org/10.2903/j.efsa.2010.1693

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Guidance on the identity, characterisation and conditions ... · Guidance on identity and characterisation of feed additives 3 EFSA Journal 20YY;volume(issue):NNNN 38 Table of contents